Previously, in studies involving a semi-homologous system of gnotobiotic newborn pigs and a virulent porcine rotavirus strain (SB-1A) and an avirulent human rotavirus strain (DS-1) and their reassortants, we demonstrated that: (i) the third (VP3), fourth (VP4), ninth (VP7), or tenth (NSP4) porcine rotavirus gene each play an important independent role in the virulence of rotavirus infection in piglets; and (ii) all four of the porcine rotavirus virulence-associated genes are required for the induction of diarrhea and the shedding of rotavirus by piglets. These observations suggested a potential new strategy for attenuation of wild-type human rotaviruses of major epidemiologic importance and its application to the development of a safe and effective vaccine. Using this strategy, we were successful in generating four human x bovine rotavirus reassortants, each of which has: (i) the VP-4 encoding gene from human rotavirus Wa (VP4:1A); (ii) VP7-encoding gene from human rotavirus D (VP7:1), DS-1 (VP7:3), or ST3 (VP7:4); and (iii) the remaining nine genes including the VP3-encoding gene and NSP4-encoding gene from bovine rotavirus UK. In addition, we successfully generated two human x bovine rotavirus reassortants, each of which had the VP4-encoding gene from human rotavirus Wa (VP4:1A) or DS-1 (VP4:1B) and the remaining genes from bovine rotavirus UK. Furthermore, we have generated two additional human x rhesus rotavirus reassortants, each of which has the VP4-encoding gene from human rotavirus Wa (VP4:1A) or DS-1 (VP4:1B), the VP7-encoding gene from human rotavirus DS-1 (VP7:2) and the remaining nine genes from rhesus rotavirus, MMU18006. More recently, we have generated an additional human x rhesus rotavirus reassortant which has ten genes from rhesus rotavirus and the VP7 gene from human rotavirus P (VP7:3). Such strains may prove to be useful for the development of an optimally effective rotavirus vaccine.